Novel steroidal 17-ketals and related compounds



United States Patent Office 3,189,605 Patented June 15, 1965 3,189,605 NOVEL STEROIDAL 17-KETALS AND RELATED CGMPOUNDS Herchel Smith, Wayne, Leland L. Smith, Malvern, and James F. Fisher, Villanova, Pa., assiguors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 24, 1962, Ser. No. 219,115 Claims. (Cl. 269-23955) wherein R represents a substituent selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, cycloalkyl, lower aralkyl and acyl; S, T and U represent a member selected from the group consisting of double unsaturated and single saturated carbon-carbon bonds,

and W represents a member selected from the group consisting of alkylenedioxymethylene, alkylenedithiomethylene and alkylenethioxymethylene, with the proviso 1) that one of S, T and U must be a double bond and the other two must be saturated single bonds; and (2) that when R is hydrogen or acyl, U must be a saturated single bond.

In the above definition of the general class of compounds of the invention, the term lower alkyl is intended to refer to those alkyl groups having from 1 to about 20 carbon atoms and more particularly to those having less than carbon atoms. The alkyl group may be normal or branched in structure, although the normal chain is generally preferred. Some examples of these would be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, octyl, dodecyl, and cetyl, to name a few. The term lower cycloallsyl refers to that substituent wherein the carbon atoms are joined in a carbocyclic ring which is generally 5 or 6 membered, but which may contain a smaller or larger number of carbon atoms subject to the practical limit of stability of such structures. The term lower aralkyl as employed herein refers in general to an alkyl substituted aromatic ring structure which may contain up to about carbon atoms in the substituted alkyl chain attached thereto. An example of this type of substituent would be for instance benzyl, phenylethyl, phenylisopropyl and the like. The term acyl as employed herein refers to a substituent derived from a mono-, di-, or polycarboxylic organic acid which may be saturated or unsaturated. These radicals are, of course, obtained from any suitable organic acid by removal of a hydroxyl group therefrom. Such acyl radicals as the alkanoyl radicals acetyl and propionyl derived from acetic and propionic acids respectively and the aryoyl radical benzoyl derived from benzoic acid would therefore serve as examples of this type of substituent.

The ketal substituent present as W in the 17-position of this novel class of compounds is considered to be an essential element of such structures. It is intended by the definition of alkylenedioxymethylene, alkylenedithiometh ylene and alkylenethi-oxymethylene as employed herein to embrace any and all forms of such ketals which can contain up to about 10 carbon atoms but preferably about 2 to 6 carbon atoms therein. These ketals can be of the closed or open chain type, both of which would behave in a similar manner. The term alkylenethioxyrnethylene involves those ketal substituents wherein both oxygen atoms have been replaced by a sulfur atom.

Some specific compounds which fall within the broad scope of the invention may be noted. To cite a few as examples one may mention compounds such as the 7- or 14-dehydroestrone 17-ethylene ketals, 6-dehydroesterone 17-ethylene ketal-3-methy1 ether, 14-dehydroestrone 17- ethylene ketal-3-methyl ether, 7-dehydroestrone 17-ethylene ketal-3-methyl ether, 14-dehydroestrone 17-ethylene ketal-B-allyl ether, 6-dehydroestrone 17-ethylene ketal-3- allyl ether, 7-dehydroestrone 17-ethylene ketal-3-allyl ether, 14-dehydroestrone 17-ethylene ketal-3-cyclopenty1 ether, 7-dehydroestrone 17-ethylene ketal-3-cyclopentyl ether, 6-dehydroestrone 17-ethylene ketal-3-cyclopentyl ether, 14-dehydroestrone l7-t1imethylene ketal 3-methyl ether, 14-dehydroestrone 17-ethylene ketal-3-acetate, 14- dehydroestrone 17-ethylene ketal 3-benzoate, 7-dehydroestrone 17-ethylene ketal-S-benzoate, 6-dehydroestrone l7-ethylene ketal-3 benzoate, 14-dehydroestrone 17-ethy1- ene thioketal 3-methyl ether, 7-dehydroestrone 17-ethylene thioketal S-methyl ether, 14-dehydroestrone 17-ethylene dithioketal, estrone 17-ethylene dithioketal 3-methyl ether, to name a few of our novel compounds.

The novel compounds of the invention may be prepared by way of several general methods of preparation. One of these may be outlined as follows:

O ?COCH3 R0 R0 i M U. 6 WU Vi (111) (IV) O n V 11 W Ro H (V) (VI) snsaaos B- In the above reaction scheme the symbol X'represents a halogen atom, while R represents one ofathe substituents previously defined. The reaction involves treatment of the g V known compound estrone methyl ether (1) with a suitable 'acylating agent such as anralkenyl acylate such asisopropenyl acetate at temperatures up to the reflux temperature'of the acylating agent for from about 2 to 24 hours duration to form the corresponding 17-enol acetate (11). The enol acetate is halogenated with a reagent suitable for introducing a halogen atom at the l-position, i.e., bromine may be employed in the presence of any suitable inert solventsuch as carbon tetrachloride to obtain the 16-halogeno substituted estrone methyl etherCilI). The

' treatment of.(III) with a suitable ketalizing agent suchas ethylene glycol and p-toluenesulfonic acid. in an' inert solvent such as benzene or the like at temperatures up. to the reflux temperature of the solvent for from 2 to 24 hours will form the 16- halogenated 17-ketal analog (IV). At this point, dehydrohalogenation of V) by treatment ,with a suitabledehydrohalogenation agent such aspotassium tertiary butoxide or the like at temperatures up tothe reflux pointof the solvent removes-the halogen's-ubsti-tuent 'and forms the A -estrone ketal (V). Treatment at this compound with ptoluenesulfonic acid causes the A bond to shift to the A -position and removes the ketalgroup to give.

the A -eStrone methyl ether (VI). This compound when ketali'zed in the same manner as above indicated for the ketalization of (III) above yields a compound (VII) of the final class of compounds disclosed and claimed as this invention wherein T is a double bond.

The compounds of the invention wherein S is a double a 7 bond may be prepared in the following manner if desired:

, In the above reaction the known compound equilin V -(VIII) is reacted witha molar equivalent quantity of a suitable ketalizing agent such as ethylene glycol and p-toluenesulfonic acid in an inert solvent such as benzene under the time and temperature conditions expressed abovefor ketalization to give the corresponding l7-ketal (IX) which is then etherified with a suitable alkylating agent to transform the hydroxy group in the 3-position to a correspending alkoxy substituent yielding the final product (X).

In still another variant of the methods of preparation of the compounds of the invention, the 17-ketals of 6-dehydroestrone and esters and ethers thereof may be obtained by following the reaction scheme hereinbelow;

4 (XII) (XIII) In the above reaction the'known compound 6r-dehy droestrone I (X1) is ketalized in the'manner above described to yield the corresponding 17-ethylene ketal (XII) which is etherified or esterified to the corresponding 3-substituted ether or ester (Xlll) by methods .Well known to the prior 'artto obtain still another variant of these novel com pounds having a A double bond. V V j, In this method of preparation in the above reaction schemeswhere it is .desiredto' prepare the -17-substituted plated for use in pharmaceutical products maybe em-. ployed in combination if desired with a large number of hemithioketal insted of the alkylenedioxy type 'a reagent such as thioethanol is'substi'tuted for alkylene glycol in the ketalizing step of the synthesis: In the same manner'where the dithio ketal is desired, areagent such as ethanedithiol is substituted for the, alkylene glycol employed in theketalizingsteps. 7 5i The compounds of the invention are usefulin the field of experimental pharmacology as well as being valuable as -interme diates for further steroid synthesisin preparing new steroidal compounds. In addition, many of the compounds of the invention have been found to demonstrate high .antilipernic properties coupled with lowfem-inizing uterine bleeding, and the like.

The novel compounds of'the invention when contemcompatible diluents, carriers, and the like to form apharmaceutical composition. Such liquid carriers as mineral oil or a lower aliphatic alcohol may be used where injectables are to be prepared. Glycerine or the like may be used where a syrup is .to be used to administer the compound. Solidexcipients, binders, xtenders or carriers 7 such as carboxymethylcellulose, starches, sugars and'the like may be employed where tablets or powders are to be employed as "a'rneans of administration. 'The dosage of the compounds will vary with the severity of the'ailment. and in general can vary from 0.5 to mg./kilo of body weight per day depending upon th many faqorsof the case involved.

The invention is further illustrated by the several fol= lowing examples of preparation of selected membersof the series. It is, of course, understood that these examples are purely by Way of illustration and are not intended to limit the scope of the invention in any manner. For a legal definition of the proper scope of the invention, attention is directed to the several appended claims.

EXAMPLE 1 1 7,1 7-efl1yZenedi0xy-3-meflzoxyestra- 1,3,5 ,14-tetraene Reflux, a mixture of 400 mg. of l4-dehydroestrone 3- methyl ether, 0.02 4 g. of p-toluenesulfonic acid monohydrate, 2.5 ml. of ethylene glycol, 0.24 ml. of ethyl orthoformate, and 60 ml. of benzene While stirring, with continuous separation of water for 7.5 hours. Wash the cooled mixture with an aqueous sodium bicarbonate solution. Dry the organic layer over anhydrous magnesium sulfate and evaporate in vacuo. The residue should Weigh 330 mg, M.P. 105113. The analytical specimen from methyl alcohol exhibits M.P. 121422;

A 287 m;t(e 2,070), A135; 3.47, 6.12, 6.23, 6.37, 6.66, 7.00, 7.98, 8.70 [a] =|-80.64c (c.=l% CHClg) chromatographically homogeneous.

AnalysisCalcd. for C I-1 0 C, 77.24; H, 8.03. Found: C, 77.42; H, 8.18.

EXAMPLE '2 3-hydroxyest1a-1 ,3,5 (10 ,14-tetmen-1 7-0ne Heat 100 mg. of 1*4-dehydroestrone 3-methyl ether and 1.5 g. of freshly prepared pyridine hydrochloride together at 210 for minutes under a nitrogen atmosphere. Cool the mixture, add 5 ml. of 5% hydrochloric acid, extract the mixture with ether, and Wash the ether extracts well with Water and With 5% potassium hydroxide solution. Acidity the alkaline extract to precipitate the product, 14- dehydroestrone, and recover by filtration.

EXAMPLE 3 1 7 ,1 7-ethylenedi0xyestra-1,3,5 (10 ,14-tetraen-3-0l Reflux ten grams of l l-dehy-drcestrone, 1.5 g. of ptoluenesulfonic acid, 750 ml. of benzene, and 100 ml. of ethylene glycol with continuous removal of water via a Dean-Stark apparatus for twenty hours. Wash the benzene solution with saturated aqueous sodium bicarbonate solution, then with Water, and finally evaporate under vacuum. Dissolve the residue in methanol, concentrate, and dilute with hexane. Precipitate the product, l4-dehydroestrone l7-ethylene ketal, and remove by filtration.

EXAMPLE 4 3 -ethoxy-1 7,1 7-ethylenedz'oxyestra-1,3,5 (10) ,14-tetraene EXAMPLE 5 3-allyl0xy-1 7,1 7-ethylenedl'0xyestra-1,3,5 (10 ,14-tetmene Dissolve one gram of l4-dehydroestrone l7-ethylene ketal 'm ml. of ethanol, and add 5 ml. of allyl bromide, together With 280 mg. of sodium hydroxide. Reflux the mixture for 20 hours, and remove the solvents under vacuum. Dissolve the residue so obtained in carbon tetrachloride, and Wash the solution with 5% sodium hydroxide solution, and then with Water. Reduce the thoroughly dried carbon tetrachloride solution in volume under vacuum until solids precipitate. Recrystallize the solids thus obtained from alcohol, thus affording the ure product, 3-

6 allyloxy 17,17 ethylenedioxyestra l,'3,5(l0),'l4 tetraene.

EMMPLE 6 3-cyclopentyl0xy-1 7 ,1 7-ethylenedi0xyestra- 1,3,5 (10),]4-tetraene Dissolve five hundred milligrams of 14-dehydroestrone l7-ethylene ketal in 25 ml. of ethanol, and add 5 ml. of cyclopentyl bromide along with 500 mg. of sodium hydroxide. Reflux the mixture overnight, and then remove the solvents in vacuo. Dissolve the dried residue in carbon tetrachloride and extract the solution thus obtained several times with 5% aqueous sodium hydroxide solution. Wash the washed organic solvent solution with distilled Water until neutral, and then remove the solvent in vacuo. Dissolve the solids therefrom in ethanol and concentrate, so as to cause deposition of the pure crystals of 3-cycl0pentyloxy-l7,17-ethylenedioxyestra 1,3,5 10) 14-tetraene.

EXAMPLE 7 3-benzyl0xy-1 7,] 7 -ethylenedi0xyesira- 1,3,5 (10 ,14-tetraene Reflux a mixture of 500 mg. of 14-dehydroestrone 17- ethylene ketal, 25 ml. of ethanol, 3 ml. of benzyl bromide, and 175 mg. of sodium hydroxide for 20 hours under nitrogen. Remove the organic solvents under vacuum, and dissolve the residue in wrbon tetrachloride. Wash the carbon tetrachloride solution with 5% sodium hydroxide solution and with water, and then evaporate under vacum. Recrystallize the solids thus obtained from methanol several times to obtain the pure product 3- benzyloxy-l7, l7-ethylenedioxyestra-l ,3 ,5 10) ,14-tetraene.

EXAMPLE 8 3 -m ethoxy-J 7,1 7-trimethylenedioxyestra- 1,3,5 (10) ,14-tetraene Treat a solution of 1.0 g. of l4-dehydroestrone 3-methyl ether in 150 ml. of dry benzene with 10 ml. of 1,3-pr0- panediol and mg. of p-toluenesulfonic acid. Reflux the mixture for 20 hours, with continuous removal of Water via a Dean-Stank apparatus, cool, and Wash with saturated sodium bicarbonate solution and with Water. Dry the benzene solution over anhydrous magnesium sulfate and concentrate in vacuo. Dissolve the solids therefrom obtained in ethyl acetate, concentrate slightly, and precipitate by the addition of petroleum ether. Recover the pure product 3-methoxy-17,17-trimethylenedioxyestra- 1,3,5 ('l0),14-tetraene by filtration.

EXAMPLE 9 17,1 7-etlzylenethi0xy-3-meth0xyestm- 1,3,5 (10) ,14-tetraene Reflux a solution of 1.0 g. of l4-dehydroestrone 3-methyl ether and 100 mg. of p-toluenesulfonic acid in ml. of dry benzene containing 1 ml. of Z-mercaptoethanol for 4 hours with continuous separation of Water from the reaction. Cool the solution, Wash with aqueous sodium bicarbonate solution and with water and dry over anhydrous magnesium sulfate. Evaporate the dried solution under vacuum to afford a crystalline residue, then crystallize several times from methanol to yield the pure 17,17- ethylenethioxy-3-methoxyestra+1,3 ,5 10) ,14-tetraene.

EXAMPLE l0 1 7,17-ethylenedithi0-3-meth0xyestra- 1,3,5 (10 ,14-tetraene Cool a mixture of 5.0 g. of '14-dehydroestrone 3-methyl ether, 5 ml. of ethanedithiol and 20 m1. of chloroform to 5. Bubble hydrogen chloride through the solution for 3 hours, and then remove the solvents under vacuum. Dissolve the solid residue so recovered in hot acetone, concentrate somewhat, and dilute with hexane to precipiand 100 ml. of methyl alcohol to 22.

7 tate the pure 17;17-ethylenedithio-3-methoxyestra-1,3,5-

(10),14-tetraene.

7 EXAMPLE 11 V 3-ac etxy-1 7,17-ethylenedi0xyesira- 1,3,5(),14tetmene Dissolve one gram of 14-de hydroestrone 17-ethylene ketal in 10 ml. of dry pyridine to which 3 ml. of acetic anhydride has been added. Keep the solution at room temperature for'18 hours, and then remove the solvents under vacuum. Crystallize the solid material thus obtained from acetone and petroleum ether to yield the pure 3-acetoxy-1'l, l7-ethylenedioxyestra-l ,3 ,5 l0) l4-tet-' raene. 7

EXAMPLE 12 i 3 -benz0yl0xy-J 7,1 7-ethyle ncdioxyestra- 1,3,5 (10 ,14-tetraene tion.

Stir and distill a mixture of 900mg. ofequilinQlOO mg. of p-toluenesulfonic acid monohydrate, and 160 ml. of

ethylene glycol over a period of 1 hour at"6 mm. pressure with a still head temperature of 83. After this peri 0d, add an additional 100 ml. of ethylene glycol and continue the distillation at 6 mm. pressure for one more hour. A volume of 230 ml. of distillate is to be collected over the two'hour-period. Cool the reaction mixture and adjust to a pH of 8.5 with an aqueous sodium bicarbonate solution. Extract the productwith ether. Dry the organic layer over anhydrous magnesium sulfate and evaporate in vacuo. Repeat crystallizations from acetonitrile so that the crude residue may yield 188 mg. of material, M.P. 155156, 7 74552.95, 3.4.2, 6.16, 6.33, e os xgig 280 111;: (6: 1,920), [u] +158.0 (o.=1% CHCla) Analysis.Calcd. for C H O C, 76.89; H, 7.74.

7 Found: C, 76.72; H, 7.42.

EXAMPLE 14 1 7 ,1 7 ethylenez lioxy-3-methoxyestrq-l ,3,5 (10) ,7-tetraene 7 Cool a solution of 1.0 g. of equilin 17-ethyleneketa1 and 12.0 g. of potassium hydroxide in ml. of water To this cooled solution, add 11.0 ml. of dimethyl sulfate with agitation over a period of 35 minutes, while maintaining the tem-.

Allow the reaction mixperature between 22 and 28.

ture to agitate at 25 for an additional 1.25 hours. Di-

lute the mixture to 500 ml. with water and cool to 10.

ml. of ethanol containing 10ml. of ethyl bromideand 700 mg. of sodium hydroxide. Continue reflux for '20 280 III 1 (6 benzene containing 2 ml. of Zmercaptoethanol,'with conhours, evaporate the organic solvent solution and :dis-' solve the solid residue in carbon tetrachloride. Wash the organic solvent solution of product with 5%. sodium hydroxide solution and then with water, and finally dry over anhydrous magnesium sulfate. Evaporatethe dried solution under Vacuum, and recrystallize the crystalline material from methanol to yield the pure'product 3-ethoxy-17, l7-ethylenedioxyestra-1,3,5 10) ,7- tetraene.

EXAMPLE '16 i I 3-allyloxy-17,17-ethylenedioxyestra-l,3,5 (10) ,Y-tetrq'ene V Reflux one gram of equilin 17-ethylene ketal, 30. ml. of ethanol, 5 ml. of allyl bromide, and 300 mg. of sodium hydroxide together for 20 hours vents under vacuum, and. dissolve the solid residue in carbon tetrachloride; wash solution with 5 sodium hy-' droxide solution'and with water until neutral. Evaporate the solvent and recrystallize the'solid product from alcohol to yield the pure 3-allyloxy-17,17-ethy1enedioxy estra-1,3,5(10),7-tetraene. a a

mide and 750 mg. of sodium hydroxide, and then remove the solvents under vacuum. Dissolve't'ne dried residue in carbon tetrachloride and Wash the solvent solution with 5%- sodium hydroxide solution and then with water. Dry the washedsolution over anhydrous magnesium sul- 3-benzyl0xy-l 7,17-ethylenedioxyestra-1,3,5 (10) ,7-

tetraene V V t Reflux for 24 hours a solution containing 1.0 g. of equilin 17-ethyle ne ketal, 5 ml. of benzylbromide, 350 mg. of sodium hydroxide in 50 ml. of ethanol. Remove the organic solvents under vacuum, and dissolve'ithe dried residue in carbon tetrachloride. Wash the carbon tetrachloride solution with 5% sodium hydroxidesolution and then with water. Remove the solvent under vacuum, and recrystallize the crystalline solids thereupon obtained several times from methanol to afford the pure Product, 3 benzyloxy 17,17-ethylenedioxyestra 1,

( ,7-tetraene.

Treat one gram of equilin 3-methyl ether dissolved in ml. of dry benzene with 60 mg. of p-toluenesulfonic acid and 10 ml. of 1,3-propanediol. I Reflux the mixture for 18 hours with continuous removal of water'via a Dean-Stark apparatus. 1 Cool the mixture, wash with saturated sodium bicarbonate solution and then with. water, dry over anhydrous magnesium sulfate, and'evaporate under vacuum; Dissolve thesolids in ethylacetate, concentrate slightly, and dliute the solution with hexane to cause precipitation of the product, 3-methoxy-17,17-

trimethylenedioxyestra-l,3,5(l0),7-tetraene and recover by filtration.

EXAMPLE 20 1 7,17-ethylenethioxy-3-meth0xyestra-1,3,5(10),7-

' tetraene i 'Refiux for 6 hours a solution of 1 g. of equilin 3-methyl 7 other and 60 mg. of p-toluenesulfonic acid in ml. of

tinuous removal of Water with a Dean-Stark apparatus.

Cool the solution, wash with saturated sodium bicarbonate Remove the sol-1 V 9 solution and then with water. Evapora-te the dried solvent solution under vacuum, and recrystallize the recovered crystallineproduct from methanol, thus to afford the pure 17,17-ethylenethioxy-3-methoxyestra-1,3,5 10) ,7-tetraene.

EXAMPLE 21 l 7,17-ethylenedithio-3-methoxyestra-J,3,5 (1 ,7 -tetraene Cool a mixture of 10 g. of equilin 3-methyl ether, 50 ml. of ethanedithiol, and 50 ml. of chloroform to 5, then bubble hydrogen chloride through the solution for 3 hours. Remove the solvents under vacuum, and dissolve the solids thus obtained in hot acetone, concentrate slightly, and cool to deposit the pure product, 17,17-ethylenedithio-3-methoxyestra-1,3,5 ,7 -tetraene.

EXAMPLE 22 3-aceZ0xy-1 7,17-ethylenedioxyestra-1,3,5(10) ,7-tetraene Dissolve l g. of equalin 17-ethylene ketal in ml. of dry pyridine, and add 5 ml. of acetic anhydride. Allow the solution to stand at room temperature for 20 hours, at which time remove the solvents under vacuum to obtain the product equilin l7-ethylene ketal 3-acetate. Recrystallize from acetone and petroleum ether to efiect further purification.

EXAMPLE 23 3-benz0yl0xy-17,17-etlzylenedioxyestra-1,3,5 (10) ,7-

tetraene EXAMPLE 24 3-metlzoxy-J 7,17-ethylenedi0xyestra-1,3,5 (1 0) ,6 tetraene Cool to 28 a solution of 1.14 g. of G-dehydroestrone 17-ethylene ketal and 11.8 g. of potassium hydroxide in 30 ml. of water and ml. of methyl alcohol. To this cooled solution add 11.0 ml. of dimethyl sulfate with agitation over a period of 35 minutes while the temperature is maintained between 28 and 30. Continue the agitation for 1.5 hours at room temperature. Dilute the mixture with water and cool to 10". Collect the resulting precipitate by filtration, wash with water and dry. The product will weigh 330 mg., M.P. 74-80". Obtain the analytical sample by repeated crystallization from methyl alcohol, M.P. 7576.

353; 3.45, 6.13, 6.24, 6.37, 6.68 xii 3P 2.21 m (e= 26,000), 261 my (6 =s,7s0), 301 mu (6 =2,320) [a 53.3.. 227.2 (c.=1% CHGIQ).

Analysis.Calcd. for C H O C, 77.27; H, 8.03. Found: C, 77.53; H, 7.92.

EXAMPLE 25 3-eth0xy-I7,17-ethylenedioxyestra-1,3,5 (l 0 ,6-tetraene obtaining the product as white crystals which can be recrystallized from methanol, yielding pure 3-ethoxy-17,17- ethylenedioxyestra-1,3,5( l0) ,6-tetraene.

1% EXAMPLE 26 3-allyloxy-l7,17-ethylerzedi0xyestra-1,3,5 (l 0) ,6-

tetraene Reflux a mixture of 500 mg. of 6-dehydroestrone 17- ethylene ketal, 15 ml. of ethanol, 2 ml. of allyl bromide, and mg. of sodium hydroxide overnight. Remove the solvents under vacuum; dissolve the residue in carbon tetrachloride and wash the solvent solution with 5% sodium hydroxide solution and then with water until neutral. Evaporate the solvent and the product recovered will be a White solid. Recrystallize from methanol to afiord the sought product 3 allyloxy 17,17 ethylenedioxyestra- 1,3,5 10) ,6-tet1'aene.

EXAMPLE 27 3-cycl0hexyl0xy-17,17-ethylenedioxyestra-1,3,5{10),6- tetraene Reflux for twenty-four hours a mixture of 2 g. of 6-dehydroestrone 17-ethylene ketal with 60 ml. of ethanol, 20 ml. of cyclohexyl bromide and 1.5 g. of sodium hydroxide. Following this remove the solvents under vacuum. Dissolve the residue containing the product 3-cyclohexyl ether and some unreacted 3-phenol in carbon tetrachloride and wash with 5% sodium hydroxide solution and then with water. Concentrate the dried organic solution under vacuum and the crystalline product 3-cyclohexyloxy-17,17- ethylenedioxyestra-1,3,5(10),6-tetraene will be recovered.

EXAMPLE 28 3-benzyl0xy-17,1 7-et hylenedi0xyestra-1,3,5 (l 0) ,6- tetraene Reflux under nitrogen for twenty hours one gram of 6- deyhdroestrone 17-ethylene ketal, 50 ml. of ethanol, 5 ml. of benzyl bromide, and 350 mg. of sodium hydroxide. Remove the organic solvents under vacuum, and dissolve the residue in carbon tetrachloride. Wash the carbon tetrachloride solution with 5% sodium hydroxide solution and then with water. After this, dry and evaporate the solution. Dissolve the residue in hot methanol and cool to precipitate the desired 3-benzyloxy-17,17-ethylenedioxyestra 1,3,5 10),6-tetraene.

EXAMPLE 29 3-meth0xy-l 7 ,1 7-trimethylenedi0xyestra-1,3,5' (l 0) ,6- tetraene Treat a solution of 1.0 g. of 6-dehydroestrone 3-methy1 ether in ml. of benzene with 60 mg. of p-toluenesulfonic acid and 10 m1. of 1,3-propanediol. Reflux the mixture for 20 hours with continuous removal of water of reaction via a Dean-Stark tube. Wash the cooled mixture with cold saturated aqueous sodium bircarbonate solution and with water. Evaporate the organic layer and recrystallize the solid residue from ethyl acetate and hexane to yield the pure product 3-methoxy-17,17-trimethylenedioxyestra-1,3,5 10) ,6-tetraene.

EXAMPLE 3 0 l 7,17-ethylenethi0xy-3-meth0xyestra-1,3,5 (l 0) ,6- tetraene Reflux for four hours a solution of 5.0 g. of 6-dehydroestrone 3-methyl ether and 300 mg. of p-toluenesulfonic acid in 800 m1. of benzene containing 5 ml. of Z-mercaptoethanol. Continuous separation of water is accomplished by means of a Dean-Stark tube. Wash the cooled solution with aqueous sodium bicarbonate solution, and evaporate the dried organic layer to dryness under vacuum. Recrystallize the crystalline residue from methanol to obtain the pure 17,17 ethylenethioxy 3 methoxyestra- 1,3,5(10),6-tetraene.

a i 5 a 7 EXAMPLEsi,

17,17-elhylenedithio-3-meth0xyestra-1,3,5(10),6- r

V tetraene 1 1 Cool to 5 a mixture of 5 g. of 6-dehydroe strone 3- methyl ether, 5 ml. of ethanedithiol and'ZO ml. of chloro- 1 'form. Bubole hydrogen chloride through the solution for three hours, then remove the solvents under vacuum. T riturate the solid residue withv a small volume of petroleum 1 ether. Filter and crecrystallize the crystalline product several times from acetone to obtain the pure 17,17-ethylenedithio-3-methoxyestra-1,3,5 10) ,6-tetraene.

We claim: 7 r 1 '1. A compound of the general structure; 1

Fill

wherein R represents a isubstituent'selected from the group consisting of hydrogen, lower alkyL-lower alkenyl, cyclo- 7 'alkyl, of up to 6 carbon atoms, benzyl, lower alkanoyl and benzoylyand W represents a member selected from" the group consisting of lower alkylenedioxymethylene of up to' 6 carbon atoms, lower alkylenedithiomethylene, of up to 6 carbon atoms and lower ralkylenethioxymethylene of up to 6 carbon atoms.

2 A compound according to claim 1 where R1 represents a lower alkyl group andW represents lower alkylenedioiry- V methylene of up to 6 carbon atoms.

3. 17,17-ethylenedioXy-3 7 methoxyestra} 1,3,5(10)',14- tetraene; r ,7 1

4. 17,-17-ethylenedioXyestra-1,3,'5( 10),14-tetraen-3-ol, t

' 5. A process for'preparing a partially dehydrogen'atedi 17-ketal of an estrogenic steroid which comprises acylating an estrone alkyl ether at the reflux temperature of the treating this compound'with:paratoluenesulfonic acid to cause the A bond to shift to a' A -position and remove a the ketal group and ketalizing by treating with a lower alkylene glycol this compound to replace the 17-ketal substituent to obtain the product of the invention.

References Cited by the Examiner *UNIT ED STATES PATENTS 6/45 Fernholz 260-3973 Fieser et al.: Steroids, pages 480-481 1951 Publishing Corp, New York.

LEWIS GOTTS, Primary Examtnera V OTHER REFERENCES Lowenthal: Tetrahedron, vol-6, pages 269-303 (19 59 7 Reinhold i UNITED STATES PATENT OFFICE J CERTIFICATE OF CORRECTION Patent No 3 189,605 June 15, 1965 Herchel Smith et al.

orrected below.

Column 5, line 20, for "287" read 277 column 6, ine 31, for "vacum" read vacuum column 8, line 63, or "dliute" read dilute column 9, line 19, for

equalin?! read equilin column 10, line 37, for ieyhdroestrone" read dehydroestrone column 12, line 10, 3r "16-hologeno" read l6-halogeno Signed and sealed this 3rd day of May 1966.

t: A EST W. SWIDER EDWARD J. BRENNER ing Officer Commissioner of Patents 

1. A COMPOUND OF THE GENERAL STRUCTURE: 